Heart-valve rings slip through FDA loophole

Nancy Stone/Chicago Tribune

Al Edwards, of Lincolnshire, underwent heart surgery in 2007 to have an annuloplasty ring stitched into his mitral valve. Only later did he learn that the ring had not been cleared by the FDA beforehand.

Al Edwards, of Lincolnshire, underwent heart surgery in 2007 to have an annuloplasty ring stitched into his mitral valve. Only later did he learn that the ring had not been cleared by the FDA beforehand. (Nancy Stone/Chicago Tribune)

Jason Grotto and Deborah L. Shelton, Tribune reporters

If you have a faulty heart valve and decide to get it replaced, a surgeon will implant an artificial one that has undergone rigorous examination by the Food and Drug Administration.

But if you choose the option recommended for most patients — repairing your valve with an annuloplasty ring — there are no such guarantees, even though both devices are permanently stitched into the heart and considered life-sustaining.

That's because, a decade ago, the FDA downgraded the regulatory class of the rings. Instead of being grouped with heart valves and implantable pacemakers, annuloplasty rings were put into a class with most catheters, sutures and hearing aids, which allows the medical device industry to gain approval for new rings without clinical studies.

"It's absolutely ridiculous. How could something that is permanently implanted in the heart be regulated this way?" said Diana Zuckerman, president of the National Research Center for Women & Families, a think tank that has fought for stricter oversight of medical devices. "The first question is: Who petitioned this change and what financial interest did they have?"

A Tribune investigation found that the FDA rubber-stamped the group's petition, allowing the invasive devices to make their way into the hearts of thousands of patients with virtually no scrutiny.

Today, annuloplasty rings have had more deaths associated with them during the past five years than any other device in their class, according to a Tribune analysis of FDA data on adverse events. Although there are many flaws in the way the FDA gathers its data and there is no way to tell if the deaths are directly related to the rings' performance, the analysis raises questions about whether the agency erred in reclassifying the device.

The newspaper's findings come amid a heated debate over the FDA's regulation of the $100 billion-a-year medical device industry.

Despite reports of illnesses, injuries and deaths linked to faulty hip and knee implants, defibrillators, and other products, new devices continue to receive far less FDA scrutiny than new drugs, and patients often are left in the dark about safety issues. The Institute of Medicine is slated to release a study this summer about how devices like the rings are cleared for use, and the FDA is expected to rewrite some of its rules soon after.

Since annuloplasty rings were reclassified, companies have introduced dozens of new models that fetch higher average prices than older ones, without having to undergo the expense or time of clinical trials. By contrast, pharmaceutical companies must fund extensive research before new drugs are approved.

The regulatory change also paved the way for at least two models of the heart rings to be implanted in more than 700 patients without clearance from the agency. In fact, the FDA didn't even know the rings existed.

Edwards Lifesciences, the California-based company that manufactured the devices, didn't submit them to the FDA for clearance, later arguing it didn't have to because the rings were slight tweaks of products that already had been cleared.

Yet the Tribune found that the company also filed patent applications for one of the rings, listing dozens of ways in which it was different than existing devices.

The agency ultimately decided that Edwards should have applied for clearance before selling them. But it did nothing to punish the company, which has seen its net income rise by 70 percent during the last three years to $218 million, according to filings with the U.S. Securities and Exchange Commission.

Edwards declined to comment on the newspaper's findings, saying through a representative that the company "followed FDA's guidance" when it sold the rings and resolved the issue "more than two years ago."

The rings are reclassified

When medical device laws were first put on the books in 1976, panels of medical experts placed every device on the market into one of three classes. Annuloplasty rings were in the highest-risk class, known as Class III, because "the device is implanted and life sustaining."

The FDA was supposed to write regulations outlining what manufacturers must do to gain premarket approval, or PMA, for each Class III device. In the meantime, Class III devices on the market before the laws were enacted could be sold through the less rigorous Class II process, known as 510k.

That had huge implications for manufacturers. Going through a PMA costs hundreds of thousands of dollars and can take years, but the 510k process can be completed in a few months and costs companies as little as a few thousand dollars.

The FDA began writing PMA rules for that group of devices in 1995. As part of the process, manufacturers could petition the FDA to reclassify devices, which the agency had grouped with devices that were "not likely candidates for reclassification."

In an interview with the Tribune, FDA officials said the agency thoroughly vetted the 1997 petition in which AdvaMed argued that annuloplasty rings should be switched into Class II.

"Our expert team of engineers, statisticians and cardiac surgeons approved the petition after considerable analysis," said Dr. Bram Zuckerman, director of the agency's division of cardiovascular devices. "We also did our own independent research and analysis and felt it was appropriate to reclassify the device."

Yet the Tribune found that the internal memo outlining the reasoning behind the agency's decision lists a single reviewer: a hydrodynamics and acoustics engineer. What's more, the memo — called a Reclassification Decision Making Document — consists entirely of paragraphs and charts lifted directly from the industry's petition.

The agency could not produce any material for the Tribune detailing any independent review or analysis of the petition. Officials said it is rare for them to issue a reclassification decision document that is taken word-for-word from a petition but that they have done so "when the petition is well-written."

The FDA and AdvaMed say the agency was justified in reclassifying annuloplasty rings, regardless of how it happened. The petition cites numerous studies finding that the rings are safe and effective and argues that medical advances have mitigated the risks associated with implanting the devices.

But not one of the studies is a clinical trial involving patients from multiple institutions randomly assigned into test groups. And many of the authors are heart surgeons who invented medical devices for and receive royalties from manufacturers.

In concluding its argument, the medical device industry wrote: "If certain testing is made prerequisite to obtaining 510k clearance for annuloplasty rings, FDA is able to maintain regulatory control over specific aspects of the device. Thus, FDA is able to reasonably assure that the product that is ultimately marketed is safe and effective."

That conclusion, verbatim, is included in the FDA's explanation of the reclassification of annuloplasty rings, which the agency announced in 2001.

Yet, less than three years later, at least two rings began to be implanted in the hearts of hundreds of people without the 510k clearance the agency said was necessary to provide safe and effective medical devices to taxpayers.

Years after surgery, patient gets a letter

During annuloplasty ring surgery, patients' hearts are stopped and bypass machines keep them alive while their chests are cut open and incisions are made in their hearts to expose the tiny valves that the rings are then stitched around.

The rings, made of metal and coated in rubber and cloth, are meant to fix faulty mitral or tricuspid valves, which regulate blood flow to and from the lungs.

If the valves don't work well, blood backs up into the chambers of the heart, which can lead to shortness of breath and, eventually, heart failure. The consensus among physicians is that repairing valves is preferable to replacing them, in part because it allows patients to avoid taking blood thinners for the rest of their lives.

The surgery was an ordeal Al Edwards, of Lincolnshire, dreaded. He had known about his regurgitating mitral valve since he was a teenager and had no symptoms. But the problem was getting worse as he grew older, and he had developed an irregular heartbeat that required surgery. So Edwards decided to have his valve repaired as well, hoping to avoid further surgery down the road.

Edwards, 61 at the time, chose to have the operation in February 2007 at Northwestern Memorial Hospital in large part because of Dr. Patrick McCarthy, a world-renowned heart surgeon there.

Two years after the surgery, Edwards received a letter from Northwestern's CEO, Dean Harrison, addressing media reports that the ring inside Edwards, a model called the Myxo ETlogix, "was experimental and not cleared by the FDA for use." The reports, Harrison said, were wrong.

Unlike most patients, Edwards knew a thing or two about FDA regulations. He has a doctorate in pharmacy and spent two decades working on drug approvals, including three years with the FDA. He filed freedom of information requests with the FDA and soon discovered that the agency hadn't cleared the device.

"I had to pick my jaw off the desk," he said. Although the ring he received apparently fixed his mitral valve, the fact that the FDA hadn't cleared the device — or even known that it existed — left him feeling betrayed.

It turns out the Myxo wasn't the only ring for which Edwards Lifesciences failed to get clearance. A second ring, called the IMR ETlogix, had been on the market since 2003 without the FDA's knowledge.

Under the law, annuloplasty rings and other devices in Class II can gain FDA clearance if the manufacturer submits paperwork that declares the products are "substantially equivalent" to existing, approved devices.

But to spare the agency a flood of paperwork, the FDA also allows new devices to forgo the clearance process if they use the same labels, technology and materials as products that already have been cleared.

Edwards Lifesciences decided that the Myxo and IMR rings fell into this category, so it never sought clearance from the FDA.

Yet, at the same time, the company submitted a patent application to the U.S. Patent and Trademark Office for the Myxo — which McCarthy co-invented — listing 40 characteristics that made the ring distinct from others on the market.

According to the patent application, McCarthy's invention was an improvement over other products because it would simplify the surgery needed to implant an annuloplasty ring. Use of the ring would make the surgery available to more patients, the application said.

The FDA says it does not review patent documents as part of its clearance process.

The IMR, meanwhile, was the only ring on the market made specifically to repair the mitral valves of patients who had experienced heart attacks.

In the end, the FDA found that Edwards Lifesciences erred when it failed to seek clearance for the devices because the shapes and materials were different than other rings on the market.

"They made changes to the devices that could impact the safety and effectiveness and, as a result, Edwards should have (sought clearance)," said Dr. Jeffrey Shuren, head of the FDA's medical device branch, who also said that the agency is working on rules to clarify when manufacturers need to apply for clearance.

The FDA cleared both the IMR and the Myxo, which had been rebranded as the dETlogix, in April 2009 without any fines or even a warning letter. FDA officials said at the time that Edwards Lifesciences, one of the largest heart device companies in the world with a market capitalization of $6.7 billion, had "made an honest attempt" to go through the proper channels but misinterpreted the law.

A month afterward, Al Edwards received a second letter from Northwestern saying his Myxo ring had been cleared by the agency — two years after his surgery.

"It really boils down to your mother, your father, your son or daughter, and whether you would want them to go through this," he said. "My answer is no, I wouldn't. I would want an approved device."